Acetyl-CoA carboxylase (ACC) is the limited enzyme in the first step of the synthesis process of fatty acid, carboxylation of acetyl-CoA with HCO3− carboxy donor in the present of ATP and Mg2+ is carried out to form malonyl coenzyme A, which is a biotin dependent enzyme.
This enzyme pertains to specific tissue enzyme in human and other mammal, which has two subtype, ACC1 and ACC2, there are some differences in tissue distribution and function between the two subtype; ACC1 ordinarily express in all tissues, the expression is most in lipogenic tissue (e.g. liver and adipose tissue), ACC2 has the highest expression in skeletal muscle and heart, and less expression in liver. Biosynthesis of long chain fatty acid is catalyzed by ACC1, acetyl-CoA is metabolized via Krebs cycle if it is not carboxylated to form malonyl coenzyme A; production of malonyl coenzyme A on cytoplasmic surface of the mitochondria is catalyzed by ACC2, the amount of fatty acid used for β-oxidation is regulated by inhibiting carnitine palmityl transferase (CPT-1).
The research shows that ACC inhibitor can inhibit ACC1 to reduce synthesis of fatty acid, and can inhibit ACC2 to promote oxidation of fatty acid in liver, and then reduce accumulation of lipid in vivo, which can effectively treat diseases or disorders associated with obesity, hypertension, diabetes, tumor, dyslipidemia and hyperlipidemia, and type II diabetes induced by liver insulin resistance caused by accumulation of lipid in liver, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).
Non-alcoholic steatohepatitis (NASH) is a chronic progressive disease induced by accumulation of lipid in liver, which can cause liver cirrhosis, liver failure and hepatocellular carcinoma. There are a lot of induction factors of NASH, e.g. age, obesity, body mass index (BMI), insulin sensitivity, dyslipidemia, hypertension and abnormally active related enzymes of liver function (e.g. alanine aminotransferase (ALT) and aspartate aminotransferase (AST)), and so on. It is reported that having metabolism syndrome symptoms (mainly centripetal obesity, hypertension, insulin resistance, high triglyceride, and low density lipoprotein) of patients is positively related to the risk of NASH. Results of liver biopsy shows that NASH accompanied by severe fibrosis in 66% diabetic or obese patients over age 50. About 12% people were deeply affected by this disease in US, the proportion increased to 22% in diabetes, more significantly, about 15˜25% NASH patients will suffer from cirrhosis, this is another reason for liver cancer second only to viral hepatitis and alcoholic hepatitis. Cirrhosis is primary reason for death caused by hepatic diseases, which directly cause hepatic decompensation and about 4% death rate every year.
Other alternative therapies for obesity, hypertension, diabetes, dyslipidemia are still needed, but for NASH, the present therapies are limited.